Abstract 371: In vivo monitoring of metabolic inhibition in anaplastic thyroid carcinoma

Abstract

Abstract Purpose/Objective(s): Anaplastic thyroid carcinoma (ATC) accounts for over half of thyroid cancer related deaths and is generally refractory to conventional treatment. Development of novel therapeutic options is critical for the management of this deadly disease. Since tumor cells fulfill energy requirements primarily through aerobic glycolysis rather than mitochondrial respiration, metabolic inhibition represents an attractive treatment modality. In vivo real time imaging may be useful for evaluating the effectiveness of targeting tumor metabolism. Materials/Methods: A panel of ATC cell lines was evaluated for dependence on glucose and glutamine for cell proliferation and survival. Intracellular ATP levels and cellular reducing potential were measured in cells treated with 2-deoxyglucose (2-DG). Enhancement of the cytotoxic effects of cisplatin and radiation therapy (XRT) with 2-DG was evaluated. In a murine orthotopic xenograft model of ATC, real-time hyperpolarized magnetic resonance imaging (HP-MRI) was employed to assess the effects of 2-DG on tumor metabolism. Results: Glucose, but not glutamine starvation, resulted in significant ATC cell death, suggesting that glucose is the primary nutrient for ATC in vitro. Alterations in extracellular glucose levels affected ATP and cellular reducing potential and both were inhibited by 2-DG. Treatment of ATC cells with 2-DG potentiated the cytotoxic effects of cisplatin alone, XRT alone or cisplatin with XRT. Dynamic spectroscopy of HP-[1-13C]-pyruvate revealed differences in the rate of conversion of pyruvate to lactate in 2-DG treated animals compared to their controls (p=0.504). Analysis with a kinetic model accounting for chemical and physical exchange highlighted this difference (p<0.001). Conclusions: Generalized dependence of ATC cells on glucose catabolism provides an opportunity to utilize metabolic inhibition to enhance sensitivity to radiation therapy and chemotherapy. HP-MRI may represent an effective means to assess metabolic targeting in vivo. Continued refinement of the kinetic parameters that relate the observed signal to multiple physical and chemical pools is necessary to facilitate interpretation of the observed changes. The synchronized optimization of metabolic inhibitors with complementary imaging agents in a preclinical platform may facilitate translation of these therapeutic options for ATC to the clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 371. doi:1538-7445.AM2012-371